Project Summary Tuberculosis (TB) is the leading infectious cause of death due to a single pathogen globally and the UN has set ambitious targets for reducing the burden of TB by 2030. TB preventive therapy (TPT) is a critical intervention for preventing TB disease and modeling studies consistently indicate that expanded TPT coverage is essential for reaching UN targets. Implementation of TPT among the populations at risk remains extremely poor, however, and new regimens that are shorter and safer than the decades-old standard of isoniazid preventive therapy are urgently needed. Over the past several decades, we have pioneered the development of short-course, rifamycin-based TPT. We demonstrated the efficacy of 3 months of weekly rifapentine and isoniazid (3HP) in people with and without HIV infection and showed that it is non-inferior to longer courses of isoniazid, with better adherence and less toxicity. This regimen is now recommended as a first-line treatment for latent TB infection by the CDC and the World Health Organization, offering the potential of substantially increased uptake of TPT as part of the END TB Strategy. More recently, supported by NIAID, we have shown that one month of daily rifapentine and isoniazid (1HP) is non-inferior to nine months of isoniazid in people with HIV infection, with higher completion rates and less toxicity. The availability of two innovative, new short- course TPT regimens offers a transformative opportunity to global TB control. The potential of a one-month regimen to catalyze uptake of TPT in high-risk populations is enormous, but data on its safety and tolerability in people without HIV infection are needed. The goal of this investigator-initiated, clinical trial application is to conduct a randomized trial comparing treatment success rates and safety of 1HP and 3HP TPT regimens in high-risk patients without HIV infection. While 3HP has been proved safe and effective in HIV-positive and ?negative people, 1HP has only been shown to be safe and efficacious in HIV-positive people. Efficacy of 1HP in non-HIV populations may be inferred based on previous experience that shows comparability of TPT regimens across risk groups, but toxicity and tolerability is not known. We will 1) compare treatment success with good adherence, documented by self-report, pill count, and pharmacologic monitoring, of 1HP compared with 3HP in HIV-uninfected adults and adolescents at increased risk of TB and 2) compare the safety of 1HP vs 3HP in this population. We hypothesize that successful treatment with 1HP will be superior to 3HP, and that the safety and tolerability of 1HP will be superior to 3HP. We will also compare the cost-effectiveness of 1HP and 3HP using a societal approach, modeling the incremental cost-effectiveness of 1HP vs 3HP, 6H, and no treatment. We hypothesize that 1HP will be cost saving vs 3HP, vs modelled costs of 6H and v no TPT. The results of this trial will be extremely valuable for establishing global and US guidelines for use of 1HP in HIV-negative people.